tbuckley/cabot-search huggingface dataset:
Abstract 3614: 3D model to study migration and invasion of lung cancer
Authors: Melina Hardt, Kurt Zatloukal, Helmut H. Popper
Journal: Cancer Research (2023)

Abstract Background: In 2D cell cultures, migration of tumor cells is characterized by epithelial-to-mesenchymal transition (EMT), whereby tumor cells loose epithelial and express mesenchymal markers and very often change into a spindle cell phenotype. In contrast to 2D cultures, in 3D cultures tumor cells do not lose their differentiation. Small cell lung cancer usually moves as single cells or in small clusters, squamous cell and adenocarcinomas preferentially move in large clusters of cells. In tissue specimen, all of these carcinomas migrate in a hybrid EMT, not loosing their cytokeratin and E-cadherin expression. In AC and SCC also polarity and specification do occur, as some tumor cells act as leaders, providing orientation for the followers. However, 3D culture system might better depict real migration and come closer to the in vivo system as 2D cell culture systems. Material and Method: A 3D bioprinter (TissueLabsR) was used to spot an alveolar-mimicking lung-specific matrix on cell culture wells. Microscopic channels out of pluronicsR are created within the matrix. Pluronics is removed by cooling, leaving empty channels within the protein matrix. These channels can be filled with different interleukins, such as IL23, which will direct migration of the tumor cells. Cultured cell lines from an adenocarcinoma (A549) and small cell carcinoma (NCI-H82) are layered on top of the matrix and migration into the matrix is studied using different time points. Results and Discussion: A matrix simulating an alveolar structure was created with MatrigelR. The A549 cells were seeded on the matrix and grown for 2,5, 10, and 14 days. The cells formed cell clusters on the matrix and after one week started to invade the matrix in cell complexes. By immunohistochemistry we could show, that the A549 cells retained their epithelial differentiation. The H82 cells showed a different behavior. They did not form large clusters, but started to invade in small groups. The use of the bioprinter enabled us not only to create a 3D tumor culture system to simulate the in vivo conditions but also to create matrix structures for studying invasion and migration and to stimulate carcinoma cells with migration-activating substances. Citation Format: Melina Hardt, Kurt Zatloukal, Helmut H. Popper. 3D model to study migration and invasion of lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3614.
Abstract 5492: Determining effects of the CD206 positive M2 macrophage depleting engineered exosome in combination with anti PD1 therapy in breast tumor
Authors: Mahrima Parvin, Mohammad H. Rashid, Ahmet Alptekin, Ali S. Arbab
Journal: Cancer Research (2023)

Abstract Introduction: Triple negative breast cancer (TNBC) subtype of breast cancer, which lacks molecular markers such as HER2 and estrogen/progesterone receptors, has limited treatment options. Exosomes are nano-sized (30-150 nm) spherical vesicles, derived from the endosomal system for intercellular communications, can be engineered to express targeting peptides to target specifically CD206 positive M2 macrophage. Investigators have used either synthetic nanoparticles or fusion protein to deliver Fc-IgG2b to initiate Antibody dependent cellular cytotoxicity (ADCC) but reports are showing a lack of ADCC following tagging with gold nanoparticles. To overcome this, in our lab, we developed engineered exosomes in non-tumorous cells, HEK293, to carry therapeutic Fc-mIgG2b to enhance ADCC and to carry peptide to deplete CD206+ M2 macrophages. We investigated the effectiveness of engineered therapeutic exosomes to target and deplete immunosuppressive CD206+ M2 macrophages in TNBC in combination with anti PD-1. Methods: In this study, we developed syngeneic metastatic TBNC model (luciferase + 4T1 cells in Balb/c) by implantation of 50K 4T1-luci cells in fat pad. On day 1 of tumor implantation, animals were treated with vehicle, engineered exosomes, anti-PD1 plus engineered exosomes, 2 dose/week for 3 weeks. They were euthanized 1 day after the last dose of treatment. Single-cell suspension was made from the primary TME, lung, and spleen. Using flow cytometry surfaces markers were investigated to determine different T-cell and myeloid cell populations. Results: We observed very surprising results following three weeks of therapies. Although the number of cytotoxic T-cells was significantly higher in the primary and metastatic TME in exosome-treated animals, there was also an increased number of proliferative T reg cells. The number of CD8+ cells was decreased following concurrent therapy with an anti-PD1 antibody. Most interestingly, lung tissue macrophages (CD11c) showed significantly increased PD-L1 expression following exosomes and anti PD1 with engineered exosomes therapies. Conclusion: This study demonstrates that treatment with engineered therapeutic exosome targeting M2 macrophages with anti PD-1 could be utilized effectively. This study will also make a greater impact in exosome engineering based targeted therapy and will open new arena to target and deplete pathogenic cell in different tumors using engineered exosome. Citation Format: Mahrima Parvin, Mohammad H. Rashid, Ahmet Alptekin, Ali S. Arbab. Determining effects of the CD206 positive M2 macrophage depleting engineered exosome in combination with anti PD1 therapy in breast tumor. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5492.
Abstract 4657: Topological data analysis reveals pan-cancer immune phenotypes with immune-related survival differences
Authors: Kevin A. Murgas, Jung H. Oh, Joseph O. Deasy, Allen R. Tannenbaum
Journal: Cancer Research (2023)

Abstract Cancer immune phenotypes present a wide range of heterogeneity across cases, with individual tumors displaying unique patterns of infiltrating immune cell types. Deconvolutional methods allow for scoring of various immune cell types in bulk tumor RNA as a quantification of immune phenotype. Understanding how immune phenotype relates to clinical outcome remains limited. Here, we demonstrate an approach applying topological data analysis to investigate differences of immune phenotype in a pan-cancer cohort (TCGA; n=11,373 tumors). We first define an Immune Activation Score based on relative abundance of activator and suppressor immune cell types and find this score depends on cancer type and distinguishes overall survival outcomes. We then implement a robust Mapper-based algorithm to delineate clusters of immune phenotypes of tumor samples across pan-cancer and within cancer types. Our method identifies immune-activated and immune-suppressed phenotypes with distinct survival outcomes and molecular features. Citation Format: Kevin A. Murgas, Jung H. Oh, Joseph O. Deasy, Allen R. Tannenbaum. Topological data analysis reveals pan-cancer immune phenotypes with immune-related survival differences. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4657.
Abstract 3250: Targeting CD38 on exhausted T cells overcomes resistance to cancer immunotherapy
Authors: Or-Yam Revach, Angelina M. Cicerchia, Moshe Sade-Feldman, Seth Anderson, Robert T. Manguso, Nir Hacohen, Russell W. Jenkins
Journal: Cancer Research (2023)

Abstract Despite the unprecedented success of immune checkpoint blockade (ICB) in melanoma and other cancers, therapeutic resistance remains a major challenge. CD38, an ecto-enzyme involved in NAD+ catabolism, is upregulated in dysfunctional/exhausted CD8+ T cells in human melanoma. As enrichment of dysfunctional CD8+ T cells is associated with lack of response to ICB, and NAD+ depletion via enhanced CD38 activity has been associated with diminished immune response, we hypothesized that CD38 might represent an attractive target to overcome resistance to ICB. While CD38 blockade has been shown to augment response to ICB in murine tumor models, the specific role of CD38 signaling in CD8 T cell exhaustion, and the therapeutic relevance of CD38 in human cancer have not been defined. Here, we confirm and extend previous observations that CD38 is enriched in exhausted CD8+ T cells during tumor progression and in response to ICB. Further, we demonstrate that disrupting CD38 signaling via neutralizing antibodies or pharmacological inhibition enhances response to ICB using established murine tumor models and patient-derived tumor explant models. Notably, we observed 54% response rate to combination PD-1/CD38 blockade using a cohort (n=35) of patient-derived organotypic tumor spheroids (PDOTS) from patients with ICB-refractory melanoma (11.4% response rate to single-agent PD-1 blockade). Supplementation of nicotinamide riboside (NR) to boost NAD+ levels mimicked the effects CD38 blockade/inhibition on PD-1 response, whereas FK866, an inhibitor of NAMPT a key step in NAD+ biosynthesis, blunted the response to combined PD-1/CD38 blockade, suggesting a major role for NAD+ in the efficacy of CD38 blockade/inhibition. Lastly, we demonstrate that in vitro CD38 inhibition/blockade in CD8+ T cells increases the levels of TCF7 (an effector/memory T cell transcription factor), decreases surface expression of co-inhibitory receptors (e.g., TIM-3, CD39, PD-1), and improves effector CD8 T cell function. Taken together, these data confirm a role for CD38 in CD8+ T cell exhaustion in melanoma and support further pre-clinical and clinical development of this novel therapeutic strategy to enhance anti-tumor immune responses. Citation Format: Or-Yam Revach, Angelina M. Cicerchia, Moshe Sade-Feldman, Seth Anderson, Robert T. Manguso, Nir Hacohen, Russell W. Jenkins. Targeting CD38 on exhausted T cells overcomes resistance to cancer immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3250.
Abstract 3989: EVI1 oncogenic role in non-canonical AR driven lethal prostate cancer
Authors: Surendra Gulla, Jonathan E. Bard, David J. VanderWeele, Kathleen Kelly, Remi Adelaiye-Ogala
Journal: Cancer Research (2023)

Abstract Background: Androgen receptor (AR) remains active in castration-resistant prostate cancer (CRPC), and AR cistrome can become extensively reprogrammed with disease progression. Recent findings from our group and others have shown an association with non-canonical AR signature with resistance to enzalutamide. However, the complete mechanism is not fully revealed. EVI1 belongs to the zinc-finger transcription factor family, and overexpression of EVI1 is associated with poor patient outcomes. However, its role in the context of resistance to AR-targeted therapy remains unclear. Our preliminary data from ChIP-seq and GSEA analysis shows a significant enrichment of EVI1 target gene-set captured from annotated enzalutamide-resistant AR binding sites. Hypothesis: EVI1 cooperates in regulating the non-canonical AR activity associated with resistance to AR targeted therapy and blocking EVI1 may overcome resistance to target therapy. Methods: Using a PDX model of advanced enzalutamide-resistant CRPC, we performed single-cell ATAC-seq + gene expression multi-omic assay. Next, we determined the enrichment of canonical vs. non-canonical AR signatures across cell populations. Using motif analysis and transcription factor foot printing, we determine EVI1 (MECOM) motif z score and enrichment. Results: Our findings demonstrate enrichment of non-canonical AR signatures in distinct population of cells following exposure to enzalutamide. In addition, the subpopulation of cells enriched for non-canonical AR cistrome also exhibited high EVI1 (MECOM) motif z-scores. Conclusion: Our data suggests a potential link between EVI1 and non-canonical AR signaling. Ongoing mechanistic studies will provide insight mechanism by which EVI1 controls non canonical AR activity and its vulnerabilities. Citation Format: Surendra Gulla, Jonathan E. Bard, David J. VanderWeele, Kathleen Kelly, Remi Adelaiye-Ogala. EVI1 oncogenic role in non-canonical AR driven lethal prostate cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3989.
Abstract 35: Development of novel human hepatocellular carcinoma models using genetically modified human hepatocytes in FSRG humanized liver mice
Authors: Marisa Carbonaro, Ciro Bonetti, Hui Huang, Kehui Wang, Mathieu Desclaux, Guochun Gong, John C. Lin, Christopher Daly, Gavin Thurston, Zhe Li
Journal: Cancer Research (2023)

Abstract The incidence of liver cancer is growing worldwide, and it is estimated that by 2025, over 1 million individuals will be affected by liver cancer every year. Hepatocellular carcinoma (HCC) accounts for about 90% of primary liver cancer cases and is one of the leading causes of death from cancer worldwide. Establishing animal models that faithfully replicate the human disease is critical to improve our understanding of HCC pathogenesis and to test new therapeutic strategies. Here, we describe a novel human HCC model using genetically modified human hepatocytes in a humanized liver mouse. Primary human hepatocytes (PHH) were modified ex vivo through lentivirus or Lipid Nanoparticle (LNP)-mediated delivery of CRISPR/Cas9 components, resulting in over-expression of oncogenes or inactivation of tumor suppressor genes. These genetically engineered PHH were engrafted into the livers of FSRG (FAH−/−, SIRPahu/hu, RAG2−/−, IL2Rg−/−) mice, developed by Regeneron VelociGene technology, in which mouse liver parenchyma can be replaced with human hepatocytes. Tumor formation was validated in livers engrafted with human hepatocytes after different combinations of genetic modification, including over-expression of cMYC plus HRASv12, and cMYC over-expression together with p53 KO. Tumor progression could be monitored by measuring human Alpha Fetoprotein (AFP) in serum of engrafted mice. Liver tumors were positive for fumarylacetoacetate hydrolase (FAH) and human Asialoglycoprotein Receptor 1 (ASGR1), confirming their human origin, as well as the proliferation marker, Ki67, and Glypican-3 (GPC3), which is frequently over-expressed in HCC and a potential therapeutic target. In these studies, mice were engrafted with a mix of lentivirus-transduced and non-transduced hepatocytes, resulting in humanized livers with both normal and transformed human hepatocytes, providing an ideal system to recapitulate neoplastic transformation and clonal expansion of human hepatocytes carrying oncogenic mutations as well as to test the specificity of novel therapies. By combining genetic manipulation of human hepatocytes with the FSRG humanized liver mouse platform, we have established a flexible system to model clinically relevant combinations of HCC mutations for both new target discovery and therapeutic testing. Citation Format: Marisa Carbonaro, Ciro Bonetti, Hui Huang, Kehui Wang, Mathieu Desclaux, Guochun Gong, John C. Lin, Christopher Daly, Gavin Thurston, Zhe Li. Development of novel human hepatocellular carcinoma models using genetically modified human hepatocytes in FSRG humanized liver mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 35.
Abstract 5693: Cancer cells subvert fibroblast function to promote a growth factor enriched tumor microenvironment in endocrine therapy resistant ER+ breast cancer
Authors: Jason I. Griffiths, Patrick A. Cosgrove, Eric Medina Castaneda, Aritro Nath, Jinfeng Chen, Frederick R. Adler, Jeffrey T. Chang, Qamar J. Khan, Andrea H. Bild
Journal: Cancer Research (2023)

Abstract While endocrine therapy (ET) has considerably improved Stage II/III ER+ breast cancer survival rates, resistance emerges in 30-50% of patients. Recent advances have uncovered numerous cancer intrinsic and tumor-microenvironment mediated mechanisms contributing to ET resistance. However, the predominant mechanisms that prevent cure and ultimately lead to development of terminal metastatic cancer remain unknown. To reveal the leading causes of ET resistance in early-stage ER+ breast cancers, we used single-cell RNA sequencing to profile serial tumor biopsies from a larger cohort of patients. Patients received either endocrine therapy (letrozole) alone or in combination with a CDK4/6 cell cycle inhibitor (ribociclib). We examined the evolution of tumor composition, cellular communication, and the phenotypic diversity of tumor-associated cancer and non-cancer cells throughout treatment. Our analyses reveal that ET-resistant tumors are fibroblast- and endothelial-enriched and consistently exhibit broad upregulation of growth factor signaling to cancer cells, with consistent activation of ERBB communication across patient tumors. Fibroblasts emerged as the primary source of these additional growth factor signals. Upregulation of fibroblast growth factor signaling (via NRG1/2, EGF and IGF) was commensurate with differentiation to a mesenchymal cancer-associated-fibroblast (myCAF) phenotype, which was itself stimulated by cancer cells through EGF and TGF signaling. In response to growth factor enrichment, cancer cells of ET-resistant tumors showed activation of MAPK signal transduction and downstream transcription factors promoting proliferation including FOS, JUN and TRIB1. These results indicate that ET resistance emerges in patient tumors when cancer cells subvert fibroblast function to promote a growth factor enriched tumor microenvironment permitting estrogen independent cancer proliferation. Citation Format: Jason I. Griffiths, Patrick A. Cosgrove, Eric Medina Castaneda, Aritro Nath, Jinfeng Chen, Frederick R. Adler, Jeffrey T. Chang, Qamar J. Khan, Andrea H. Bild. Cancer cells subvert fibroblast function to promote a growth factor enriched tumor microenvironment in endocrine therapy resistant ER+ breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5693.
Abstract 6568: Extended support for model organisms: The next frontier for the molecular signatures database
Authors: Anthony S. Castanza, Jill M. Recla, David Eby, Alexander T. Wenzel, Helga Thorvaldsdottir, Carol J. Bult, Jill P. Mesirov
Journal: Cancer Research (2023)

Abstract In 2005, we introduced the Gene Set Enrichment Analysis (GSEA) method to enable the identification and estimation of significance of activated biological pathways and processes in molecular data. Serving a community of over 300,000 registered users, and contributing scientific analysis to more than 30,000 publications, GSEA has become ubiquitous in gene expression analysis and particularly in cancer research. The power of GSEA relies, in a large part, on the Molecular Signatures Database (MSigDB) that provides tens of thousands of expertly curated and annotated gene sets representing cellular processes, canonical pathways, response signatures, etc., derived from prior studies, public data, and curated pathway databases. Here we describe an important recent addition to the GSEA/MSigDB resource. Historically, the GSEA-MSigDB resource has focused specifically on human data, offering guidance and support for analysis of model organism data through limited provision of orthology mapping files. In recognition of the importance of the mouse as a model organism for cancer research, we recently significantly expanded our support for mouse data in two ways. (1) We introduced Mouse MSigDB with a total of about 15,000 sets that are provided in the native mouse gene symbol space and are derived from published mouse datasets and mouse-focused resources. This allows GSEA analysis of mouse datasets without the need for orthology conversion. (2) For investigators who wish to use MSigDB’s human gene sets to analyze mouse data, or vice versa, we also implemented a new procedure for orthology mapping gene identifiers in an input dataset to match the identifiers of the gene sets. The new mapping considers the particular requirements of gene set enrichment analysis, and incorporates high confidence gene ortholog data from the Alliance of Genome Resources and ortholog-match refinement utilizing Ensembl’s ortholog datasets. Together, these new additions offer a substantial step forward for making mouse a first-class citizen of the GSEA-MSigDB ecosystem. The new Mouse MSigDB, and the full GSEA-MSigDB resource, is available at gsea-msigdb.org. Citation Format: Anthony S. Castanza, Jill M. Recla, David Eby, Alexander T. Wenzel, Helga Thorvaldsdottir, Carol J. Bult, Jill P. Mesirov. Extended support for model organisms: The next frontier for the molecular signatures database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6568.